Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[N:17][N:16](COCCOC)[C:13]3=[N:14][CH:15]=2)[CH:5]=1.B(F)(F)F.CCOCC>ClCCl>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[N:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:5]=1
Reactant: COCCOCn1nc(-c2ccccc2OC)c2cc(-c3cccc(C(=O)OC)c3)cnc21
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1cccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A solution of 3-[1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid methyl ester (573 mg, 1.28 mmol) in dichloromethane (25 mL) was cooled down to 0-5° C. and boron trifluoride etherate (0.8 ml, 6.4 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 16 h. A yellow precipitate was formed was filtered off to afford 3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid methyl ester (110 mg (0.29 mmol; 23% yield). 1H-NMR (500 MHz, d6-DMSO) δ8.88 (d, 1H), 8.39 (d, 1H), 8.27 (t, 1H), 8.06 (td, 1H), 7.99 (td, 1H), 7.65-7.68 (m, 2H), 7.48 (ddd, 1H), 7.23 (d, 1H), 7.11 (dt, 1H), 3.90 (s, 3H), 3.87 (s, 3H). MS: m/z 360 [MH+].
Reaction SMILES: [Sn].[CH:2]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[N+:14]([O-])=O)([CH3:4])[CH3:3].Cl.C(O)(=O)C>CCOCC>[CH:2]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[NH2:14])([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc([N+](=O)[O-])c(C(C)C)c1
Agent: Cl
Agent: [Sn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)c1ccc(N)c(C(C)C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Mossey Tin (22 g, 184.5 mmol) was added to a solution of Intermediate 32 (25 g, 120 mmol), followed by conc. HCl (150 mL). After heating at 100° C. for 1 hour, acetic acid (50 mL) was added to the mixture and it was heated for another 30 minutes. After stirring at room temperature overnight, the reaction mixture was diluted with ether (500 mL), washed with water (50 mL) and transferred to a 500 mL beaker. Solid potassium carbonate was carefully added until all acids were quenched (˜80 g). The mixture was then extracted with ether (3×100 mL), washed with brine (1×20 mL), dried (Na2SO4) and concentrated to give the title compound in a crude form as a brown oil that was taken to the next step without further purification:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:21][CH2:22][N:23]([C:6]([C:5]2[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=2[CH3:11])=[O:8])[CH2:24][CH2:25]1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Yield: 83.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 6-fluoro-4-methylnicotinic acid (500 mg) and 1-(2,4-dimethylphenyl)piperazine (607 mg), the title compound (870 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][N:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=2)[CH:17]=[CH:16][N:15]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: COc1cc(-c2ccc(C(F)(F)F)nn2)ccn1
Yield: 60.2 %

Procedure:
3-Chloro-6-(trifluoromethyl)pyridazine (137 mg, 0.751 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (176 mg, 0.749 mmol) were reacted according to Example 31 (step a) to provide the title compound (115 mg, 60%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.39 (d, J=5.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.62 (dd, J=5.4, 1.5 Hz, 1H), 7.45 (s, 1H), 4.03 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br.[Br:13][CH2:14][CH2:15][NH2:16].C(N(CC)CC)C>ClCCl.O>[Br:13][CH2:14][CH2:15][NH:16][S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: NCCBr
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCBr)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Fluoro benzene sulfonyl chloride (8 g, 0.0411 mol) was added dropwise at 0° C. to a solution of 2-bromoethylamine hydrogen bromide (10.27 g, 0.0501 mol) and triethyl amine (14.3 ml, 0.1029 mol) in dry dichloromethane (100 ml) and stirred at room temperature for 1 h under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate. Organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded the sub-title product as a liquid. Yield: 11 g
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:19](=[O:20])[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25](C4C=CC=CC=4C#N)=[CH:24][CH:23]=3)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]3[N:39]=[CH:40][N:41]=[C:15]23)[CH2:10][CH2:9]1)=[O:7])(=O)[CH3:2].[C:42]1([CH3:52])[CH:47]=[CH:46][C:45](S(Cl)(=O)=O)=[CH:44][CH:43]=1.[N:53]1C=CC=CC=1>C(OCC)(=O)C>[CH3:2][C:1]1[O:7][C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[C:19](=[O:20])[C:18]([CH2:21][C:22]4[CH:23]=[CH:24][C:25]([C:43]5[C:42]([C:52]#[N:53])=[CH:47][CH:46]=[CH:45][CH:44]=5)=[CH:26][CH:27]=4)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]4[N:39]=[CH:40][N:41]=[C:15]34)[CH2:10][CH2:9]2)=[N:5][N:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccncc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)NNC(C)=O)CC2)c2ncnn12
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3nnc(C)o3)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A mixture of trans-N′-acetyl-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarbohydrazide (0.4 g), p-toluenesulfonyl chloride (0.42 g) and pyridine (10 mL) was stirred at 110° C. for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.33 g, 85%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1(C)C=CC(S([N:16]2[C:32]3[C:19]4=[C:20]([CH:29]=[CH:30][CH:31]=3)[C@H:21]3[O:26][CH2:25][C:24](=O)[NH:23][C@@H:22]3[CH2:28][C:18]4=[CH:17]2)(=O)=O)=CC=1.O>O1CCCC1>[CH:29]1[C:20]2[C@H:21]3[O:26][CH2:25][CH2:24][NH:23][C@@H:22]3[CH2:28][C:18]3[C:19]=2[C:32]([NH:16][CH:17]=3)=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(cccc42)[C@H]2OCC(=O)N[C@@H]2C3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1cc2c3c(c[nH]c3c1)C[C@H]1NCCO[C@H]21
Yield: 41.6 %

Procedure:
To a stirred slurry of lithium aluminum hydride (3.0 gms) in tetrahydrofuran (200 ml) is added trans-4-(p-tolylsulphonyl)-4,6,6a,8,9,10a hexahydro-7H-indolo-[3,4-gh]-[1,4]-benzoxazin-8-one (3.0 gms) in portions over 5 minutes. The resulting mixture is refluxed for 17 hours. The cooled slurry is hydrolyzed with water (6 ml), and the organic phase is separated from the solid inorganics by filtration. The solid is rinsed with ether (3×100 ml). The organic solvents are dried over anhydrous sodium sulfate. After filtration, the solvents are removed under reduced pressure (20 mm). The resulting oil is purified by column chromatography silica; CHCl3 (sat. with NH4OH) to yield 700 mg of trans 4,6,6a,8,9,10a-Hexahydro-7H-indolo-[3,4 gh]-[1,4]-benzoxazine; which after recrystalization from methanol gives 540 mg (25%) m.p. 175°-177° C. with previous softening.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:24][CH:23]=[CH2:22])[C@@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2cc(Br)ccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(C(=O)OC(C)(C)C)[C@@H]1CCc2cc(Br)ccc2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
((R)-6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (3.26 g, 10 mmol) was dissolved in dimethylformamide (30 ml). Sodium hydride (50% in oil) (528 mg, 11 mmol) was added and stirred for 15 minutes at room temperature. Allyl bromide (0.95 ml, 11 mmol) was added and the reaction mixture was stirred at room temperature overnight. To the reaction mixture was added H2O (400 ml) and extracted twice with 150 ml diethylether. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield the crude product (3.25 g). The crude product was purified with silica gel chromatography with cyclohexane/ethyl acetate (9:1) as eluent, yielding the purified product (2.7 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[N:4]([CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]([NH:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[C:2]([Cl:1])=[N:3][N:4]3[CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:35])=[CH:31][CH:32]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: Nc1cccc2c1c(Cl)nn2CCN1CCCC1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)Nc1cccc2c1c(Cl)nn2CCN1CCCC1
Reaction time: 6 h

Procedure:
A mixture of 3-chloro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-4-ylamine (300 mg, 1.14 mmol), (4-benzyloxy-phenyl)-acetic acid (302 mg, 1.25 mmol), ethyldimethylpropylcarbodiimide hydrochloride (261 mg g, 1.37 mmol), N-hydroxybenzotriazole (184 mg, 1.37 mmol), N-methyl morpholine (290 mg, 2.72 mmol) in 5 mL of DMF was stirred for 6 hours and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, triethylamine/ethyl acetate, 1/10) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 1.60 (m, 4H), 2.43 (m, 4H), 2.85 (t, 2H, J=6.44), 3.69 (s, 2H), 4.48 (t, 2H, J=6.44), 5.10 (s, 2H), 6.99 (d, 2H, J=8.81), 7.28–7.48 (m, 9H), 7.59 (m, 1H), 10.10 (s, 1H); MS (DCI/NH3) m/z 489 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][C:21]3[CH:22]=[C:12]([CH:13]=[CH:14][CH:23]=3)[C:4]#[N:3])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.088 g, 0.19 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.26 (s, 2 H) 7.21 (s, 1 H) 7.29 (d, J=5.15 Hz, 1 H) 7.55 (m, 2 H) 7.65 (d, J=8.09 Hz, 1 H) 7.78 (m, 3 H) 7.94 (m, 2 H) 8.22 (d, J=5.52 Hz, 1 H) 14.19 (s, 1 H) 14.83 (s, 1 H). MS (ESI−) m/z 476(M−H)−.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[C:10]([CH3:24])=[C:11]([CH3:23])[C:12]2[O:16][CH:15]([CH2:17][CH2:18][CH2:19][OH:20])[S:14][C:13]=2[C:21]=1[CH3:22].[CH3:25][O:26][CH2:27]Cl>C1C=CC=CC=1.O>[CH3:25][O:26][CH2:27][O:8][C:9]1[C:10]([CH3:24])=[C:11]([CH3:23])[C:12]2[O:16][CH:15]([CH2:17][CH2:18][CH2:19][OH:20])[S:14][C:13]=2[C:21]=1[CH3:22]
Reactant: COCCl
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCO)O2
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1c(C)c(C)c2c(c1C)SC(CCCO)O2

Procedure:
340 mg of a 55% w/w oily suspension of sodium hydride was added to 20 ml of dimethylformamide, followed by 2.0 g of crystals of 3-(5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)propanol (prepared as described in Example 71), with ice cooling and under a stream of nitrogen. The reaction mixture was then cooled with ice for 30 minutes, after which it was allowed to react for 1 hour at room temperature; it then was again cooled with ice. A solution of 630 mg of chloromethyl methyl ether in 2 ml of benzene was then added dropwise, after which the temperature of the reaction mixture was gradually raised and the reaction mixture was allowed to react further for 20 hours at room temperature. The reaction mixture was then poured into water and extracted with benzene. The extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel Lobar column chromatography. The title compound was obtained from the fraction eluted with a 9:1 by volume mixture of benzene and ethyl acetate.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.[CH:13]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH2:16]CC1.BrCC#CC.Cl>CCCCCC.O1CCCC1>[CH3:4][C:3]#[C:2][CH2:1][C:13]1([C:19]([OH:21])=[O:20])[CH2:16][CH2:17][CH2:18]1
Reactant: O=C(O)C1CCCCC1
Reactant: [Li]CCCC
Agent: CC#CCBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC#CCC1(C(=O)O)CCC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
At -30° C., 265 ml of 1.66-molar butyllithium solution in hexane is added to a solution of 44.52 g of diisopropylamine in 200 ml of tetrahydrofuran, and thereafter 20.02 g of cyclohexanecarboxylic acid is added thereto. The mixture is stirred for 30 minutes at -10° C. and then 31.92 g of 1-bromo-2-butyne is added dropwise and the mixture is agitated for 16 hours at 25° C. whereupon it is poured on 600 ml of ice water. After acidifying with 2N hydrochloric acid to pH 4, the mixture is extracted with ether, the extract is washed with brine, dried over magnesium sulfate, and the the evaporated under vacuum. The residue is purified by distillation, thus obtaining 18 g of 2,2-trimethylenehex-4-ynoic acid (bp 140° C.-143° C., 15 torr).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O[CH:29]1CCCNC1.CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:29][CH2:25][CH:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC(O)C2)c(Br)c1
Temperature: 25 °C

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35, 1 g, 2.53 mmol), 3-hydroxypiperidine (307 mg, 3.03 mmol) and DIPEA (883 μL, 5.06 mmol) in iPrOH (2528 μL) were added to a MW vial and subjected to MW irradiation at 140° C. for 60 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure, treated with 0.5 M HCl (25 mL) and extracted with EtOAc. The combined extracts were washed with HCl 0.5 M, brine, dried over MgSO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (Silica gel column, 24 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1)), from 15% to 60% EtOAc-EtOH+0.1% NH4OH (9:1)) to afford the title compound as a white foam. UPLC-MS (condition 1) tR=2.89 min, m/z=460.0-462.0 [M+H]+, m/z=458.0-460.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.45 (m, 1H) 1.46-1.66 (m, 1H) 1.73-1.87 (m, 1H) 1.89-2.01 (m, 1H) 2.74 (dd, J=12.23, 9.29 Hz, 1H) 2.92 (t, J=10.64 Hz, 1H) 3.56-3.70 (m, 1H) 3.70-3.81 (m, 1H) 3.91 (dd, J=12.10, 3.30 Hz, 1H) 4.87 (d, J=4.40 Hz, 1H) 7.36 (d, J=8.56 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.42 (d, J=1.96 Hz, 1H) 8.76 (d, J=1.96 Hz, 1H) 10.37 (s, 1H).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[CH3:7].[Cl:15][C:16]1[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].[Cl-].[NH4+]>CCCCCC.O1CCCC1.O>[CH2:6]([O:8][CH2:9][N:10]1[C:14]([CH:18]([OH:19])[C:17]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[C:23]([Cl:24])[C:16]=2[Cl:15])=[CH:13][CH:12]=[N:11]1)[CH3:7]
Reactant: CCOCn1cccn1
Reactant: COc1ccc(C=O)c(Cl)c1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOCn1nccc1C(O)c1ccc(OC)c(Cl)c1Cl
Reaction time: 1 h
Yield: 81.5 %

Procedure:
4.13 ml of 1.6M n-butyl lithium in hexane are added dropwise to a tetrahydrfuran solution of 0.76 g of 1-ethoxymethylpyrazole at -60° C. under argon gas atmosphere. the mixture is stirred at -63° to -50° C. for 1 hour. A solution of 1.23 g of 2,3-dichloro-4-methoxybenzaldehyde in tetrahydrofuran is added to the mixture, and the mixture is stirred at -50° C. to room temperature for 1 hour. An aqueous saturated ammonium chloride solution and water are added to the mixture under ice-cooling and the mixture is concentrated to remove tetrahydrofuran. The residual aqueous layer is extracted with ethyl acetate and the extract is washed with water, dried and evaporated to give colorless crystals, which are then washed with isopropyl ether and dried to give 1.62 g of α-(1-ethoxymethyl-5-pyrazolyl)-2,3-dichloro-4-methoxy-benzylalcohol.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:27][C:26]([C:28]([O:30]C)=[O:29])=[CH:25][CH:24]=1.[OH-].[Na+].CO>O>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)o1
Yield: 97.3 %

Procedure:
A solution of methyl 5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate (5.5 g, 13.0 mmol) and sodium hydroxide (1.04 g, 26.0 mmol) in water 100 ml) and methanol (40 mL) was stirred at 65° C. for 16 h. The solvent methanol was evaporated under reduced pressure, and the residue was cooled in ice-bath and acidified with 10% hydrochloric acid to pH 1-2. The solid precipitate was filtered off, and recrystallized from ethanol (100 mL) to afford 5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid (5.10 g, 92%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.36-6.92 (m, 5H), 6.51 (s, 1H), 6.44 (d, J=3.5 Hz, 1H), 6.40 (s, 1H), 5.02 (ABq, 2H), 4.81 (ABq, 2H), 4.51 (t, J=8.6 Hz, 2H), 3.04-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.2, 161.6, 160.9, 159.6, 153.7, 145.0, 142.1, 132.7, 129.1, 124.0, 123.7, 121.0, 120.4, 119.6, 119.1, 111.1, 109.7, 92.9, 80.0, 72.6, 57.4, 37.3, 28.8; MS (ES+) m/z 403.8 (M+1).
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].C(OC([NH:15][C@@H:16]([CH2:51][CH2:52][CH2:53][CH2:54][NH:55]C(OC(C)(C)C)=O)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=1[C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([NH2:39])[N:33]=[C:32]2[C:40]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)=[O:41])=[O:18])=O)(C)(C)C.CCCCCCC>ClCCl>[CH:3]([OH:5])=[O:4].[NH2:15][C@@H:16]([CH2:51][CH2:52][CH2:53][CH2:54][NH2:55])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=1[C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([NH2:39])[N:33]=[C:32]2[C:40]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)=[O:41])=[O:18]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Solvent: ClCCl
Solvent: CCCCCCC
Product: NCCCC[C@H](N)C(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Product: O=CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
515 μl of trifluoroacetic acid are added to 1.8 g of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4,5-difluorobenzyl (S)-2,6-bis-tert-butoxycarbonylaminohexanoate in 50 ml of dichloromethane with ice-cooling. The mixture is subsequently stirred at 25° C. for a further 16 h, 20 ml of n-heptane are added, and the mixture is subsequently evaporated to dryness in vacuo. The residue is dissolved in 4 ml of acetonitrile and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[CH3:20][C:21]1[CH:22]=[C:23]([CH2:24][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Cc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-methylbenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-methylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][N:9]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].C(N(CC)CC)C>O1CCCC1.ClCCl>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:19]([O:20][CH3:21])[CH3:18])=[O:13])=[CH:10][N:9]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
Oxalyl chloride 12.1 g (95.2 mmol) was added dropwise to a solution of 6-chloronicotinic acid 10.0 g (63.5 mmol) in 100 mL tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h, and then concentrated to give a residue, which was dissolved in 50 mL dichloromethane. The solution thus formed was added to a solution of N,O-dimethylhydroxylamine hydrochloride 12.4 g (126.9 mmol) and triethylamine 25.7 g (253.9 mmol) in 100 mL dichloromethane, stirred at room temperature for 1 h., concentrated, and purified by column chromatography to afford the desired product as colorless oil (9.4 g, 73.8% yield).